Diabetes is increasingly recognized to be influenced by complex genetic and metabolic factors involving multiple organs and molecules. A single important molecule may directly or indirectly control the function of other molecules and multiple tissues. The function of an adult tissue is clearly dependent upon its history, i.e., its differentiation and development, as well as upon signals emanating from other tissues and the environment. This Program Project Grant involves five outstanding investigators, each focused on a specific molecule that regulates development and metabolic function of a specific tissue. Project 1 (Lazar) addresses the role of resistin, a novel adipocyte-secreted factor (adipokine), in insulin resistance and atherosclerosis. Project 2 (Ahima) examines the role of the central nervous system in mediating the metabolic effects of adipokines, focusing on adiponectin, leptin, and resistin. Project 3 (Birnbaum) investigates the regulation of metabolism by Akt/PKB in beta cell and the brain. Project 4 (Kaestner) addresses the role of the Foxa family of transcription factors, as well as coactivators, in liver metabolism. Project 5 (Staffers) focuses on regulation of pancreatic development and differentiation by the homeodomain transcription factor PDX. Each individual project addresses an important hypothesis using molecular and genetic tools, including in vivo mutational analysis. A particularly exciting aspect of this proposal is its tremendous potential for synergism. Frequent interactions will maximize the opportunities for new discoveries related to obvious or surprising interactions between this variety of molecules and metabolic tissues. These interactions will be facilitated by a collaborative environment at the University of Pennsylvania;the close physical proximity of the investigators;an administrative core that coordinates frequent meetings among the investigators and with scientific visitors;an outstanding morphology core in a dedicated central space that encourages physical and intellectual interactions via the technical director and shared personnel;and embryonic stem cell core and metabolic phenotyping cores that facilitate interactions and rapid dissemination of new results, techniques, and ideas. The proposed studies will address major and specific questions relevant to diabetes and metabolic diseases. At the same time, the specific investigators, environment, and format of this proposal facilitate interactions that should enhance the discovery process. There is an excellent likelihood that advances made by this program project group will have a positive impact on the epidemics of diabetes and metabolic diseases that are ravaging our society.